Daily Respiratory Research Analysis

Respiratory viruses can cause severe infections, often leading to hospitalization or death, and pose a major pandemic threat. No broad-spectrum antiviral is currently available. However, most respiratory viruses use sialic acid or heparan sulfates as attachment receptors. Here, we report the identification of a pan-respiratory antiviral strategy based on mimicking both glycans. We synthesized a modified cyclodextrin that simultaneously mimics heparan sulfate and sialic acid. This compound demonstrated broad-spectrum antiviral activity against important human pathogens: parainfluenza virus 3, respiratory syncytial virus, influenza virus H1N1, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, the compound is active against avian strains of influenza virus, revealing its importance for pandemic preparedness. The compound retains broad-spectrum activity in ex vivo models of respiratory tissues and in vivo against respiratory syncytial virus and influenza virus, using prophylactic and therapeutic strategies. These findings contribute to the development of future treatments and preventive measures for respiratory viral infections.

Staphylococcus aureus is a leading cause of healthcare-associated pneumonia, contributing significantly to morbidity and mortality worldwide. As a ubiquitous colonizer of the upper respiratory tract, S. aureus must undergo substantial metabolic adaptation to achieve persistent infection in the distinctive microenvironment of the lung. We observed that fumC, which encodes the enzyme that converts fumarate to malate, is highly conserved with low mutation rates in S. aureus isolates from chronic lung infections. Fumarate, a pro-inflammatory metabolite produced by macrophages during infection, is regulated by the host fumarate hydratase (FH) to limit inflammation. Here, we demonstrate that fumarate, which accumulates in the chronically infected lung, is detrimental to S. aureus, blocking primary metabolic pathways such as glycolysis and oxidative phosphorylation (OXPHOS). This creates a metabolic bottleneck that drives staphylococcal FH (FumC) activity for airway adaptation. FumC not only degrades fumarate but also directs its utilization into critical pathways including the tricarboxylic acid (TCA) cycle, gluconeogenesis and hexosamine synthesis to maintain metabolic fitness and form a protective biofilm. Itaconate, another abundant immunometabolite in the infected airway enhances FumC activity, in synergy with fumarate. In a mouse model of pneumonia, a ΔfumC mutant displays significant attenuation compared to its parent and complemented strains, particularly in fumarate- and itaconate-replete conditions. Our findings underscore the pivotal role of immunometabolites in promoting S. aureus pulmonary adaptation.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe form of lung failure with a high mortality rate and no effective pharmacological therapy. Although the cellular and molecular mechanisms involved in ARDS onset have been extensively studied, those governing its resolution remain unclear. Recent human cohort studies have suggested an association between ARDS severity and low blood basophil count. Therefore, in this study, we investigated the roles of basophils in ARDS pathogenesis and resolution. METHODS: We examined the effects of basophil depletion in lipopolysaccharide-induced ARDS model mice and assessed the roles of basophils in ARDS onset and resolution using genetically engineered mice and single-cell RNA-sequencing analysis. RESULTS: Intratracheal administration of lipopolysaccharides induced severe lung inflammation, characterised by extensive neutrophil infiltration, followed by gradual recovery to homeostatic conditions. Basophil depletion impaired the resolution but not the induction of lung inflammation, highlighting the critical role of basophils in the resolution phase of ARDS. Basophils accumulated in the lungs were the primary sources of the cytokine interleukin (IL)-4. Mice with basophil-specific IL-4 deficiency failed to resolve lung inflammation, as did mice with neutrophil-specific IL-4 receptor deficiency. Transcriptomic analysis revealed that basophil-derived IL-4 acted on neutrophils to suppress the anti-apoptotic gene and pro-inflammatory mediator expression. CONCLUSIONS: Overall, our findings revealed that basophils played essential roles in the ARDS resolution phase, primarily by producing IL-4, which acted on neutrophils to alleviate lung inflammation in ARDS model mice.